[unreadable] Colorectal cancer remains the third leading cause of cancer deaths in the United States and a growing problem in the developing world. Of the patients who die from colorectal cancer, most will succumb with metastatic disease. Nearly 50% of patients diagnosed with colon cancer develop metastases within five year. Most commonly these tumors metastasize to the liver. Often this metastatic burden appears remote in time from a patient's initial presentation and treatment for their primary tumor. This phenomenon poses important questions about the biology of metastases and presents significant therapeutic dilemmas. Important strides have been made clinically in the field of colorectal cancer, notably in early detection of lesions and adjuvant therapy for resected tumors. However, further advances are needed to effectively address metastatic disease. The molecular mechanisms governing the growth and proliferation of distant metastases of colon cancers are only beginning to be elucidated. This R03 application will build upon work begun in the K08 proposal entitled "Role of Metalloproteinases in Colon Cancer Metastases". A significant focus of the study of metastases has been on controlling later stages of an advanced tumor. Our goal has been to identify the earliest steps in late stage disease as targets for intervention. Advanced techniques in multiphoton microscopy will be employed in this proposal to visualize early interactions of colorectal cancer cells with the liver microenvironment. Attention will focus on tumor cell adhesion and arrest in the liver vasculature, extravasation or alternatively growth of micrometastases in the vasculature, and the early steps in angiogenesis in small tumor colonies. We will investigate the role of stromal derived MMP-9 in these processes as previous data has demonstrated an important role for MMP-9 in the growth of colorectal metastases in the liver. In this R03 proposal, we will examine the earliest steps in the establishment of metastatic colon cancer in the liver. Sophisticated microscopy techniques will be used to analyze interactions of single cells and small groups of cells in the liver microenvironment. A better understanding of the initiating events in metastasis will allow for improved targeted therapies for late stage cancers. [unreadable] [unreadable]